The present invention is related to an amphiphilic polymer network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers and to methods for preparing the networks. The present invention is more particularly related to an amphiphilic polymer network comprising the reaction product of telechelic three-arm star polyisobutylene hydrophobic crosslinking agents and acrylate or methacrylate hydrophilic monomers, and implantable biological devices comprising the amphiphilic networks which are capable of encapsulating and immunoisolating biologically active moieties, such as cells, from the immune response of a host individual.
Many medical deficiencies and diseases result from the inability of an individual""s cells to produce normal biologically active moieties. Many of these deficiencies can be remedied by providing an exogenous source of needed biologically active moieties or pharmacological agents to the individual having the deficiency. A well known example of a disease that can be remedied by providing an exogenous source of a biological material or pharmacological agent is Type I diabetes mellitus, wherein the production of insulin by pancreatic Langerhans islets is substantially deficient, impaired or completely lost.
Encapsulation of human islet cells or tissues within a biologically compatible (biocompatible) device, such as a reservoir or physical barrier, followed by implantation of the device within an individual has been proposed to deliver biological material to an individual to treat Type I diabetes and other disease states. However, the immune response of the host, and consequently graft rejection of biological material, such as cells, tissues and organs has severely limited the use of implantation of such materials into individuals.
The supply of porcine pancreatic islet cells is much greater than human pancreatic islet cells and, therefore, a xenograft of porcine islet cells, if effectively immunoisolated from the normal immunological response of a human, would be of great benefit to a vast number of diabetic patients.
Amphiphilic polymer networks have been targeted as potential materials that are useful for implantation of biologically active moieties. An amphiphilic polymer network is a random assemblage of hydrophilic and hydrophobic polymer chains that is able to swell in both hydrophilic solvents (e.g., water) and hydrophobic solvents (e.g., a liquid hydrocarbon). Amphiphilic polymer networks have been disclosed in the prior art. U.S. Pat. Nos. 4,486,572 and 4,942,204 to Kennedy, U.S. Pat. No. 5,073,381 to Ivan, Kennedy and Mackey, and in Keszler and Kennedy, Journal of Macromolecular Science, Chemistry Edition, Vol. A21, No. 3, pages 319-334 (1984).
U.S. Pat. No. 4,486,572 to Kennedy discloses the synthesis of styryl-telechelic polyisobutylene and amphiphilic networks comprising the copolymerization product of the styryl-telechelic polyisobutylene with vinyl acetate or N-vinyl-2-pyrollidone.
U.S. Pat. No 4,942,204 to Kennedy discloses an amphiphilic copolymer network swellable in water or n-heptane but insoluble in either, comprising the product of the reaction of an acrylate or methacrylate of dialkylaminoalkyl with a hydrophobic bifunctional acryloyl or methacryloyl capped polyelofin. The preferred embodiment disclosed is an amphiphilic network having been synthesized by free-radical copolymerization of linear hydrophobic acrylate (A-PIB-A) or methacrylate (MA-PIB-MA) capped polyisobutylenes with 2-(dimethylamino)ethyl methacrylate (DMAEMA).
U.S. Pat. No. 5,073,381 to Ivan et al., a continuation-in-part of U.S. Pat. No. 4,942,204, discloses various amphiphilic copolymer networks that are swellable in water or n-heptane that comprise the reaction product of a hydrophobic linear acryloyl or methacryloyl capped polyolefin and a hydrophilic polyacrylate or polymethacrylate, such as N,N-dimethylacrylamide (DMAAm) and 2-hydroxyethyl methylmethacrylate (HEMA).
U.S. Pat. No. 4,085,168 to Milkovich et al. describes chemically joined, phase-separated self-cured hydrophilic thermoplastic graft copolymers which are copolymers of at least one hydrophilic (water soluble) ethylenically unsaturated monomer or mixture thereof and at least one copolymerizable hydrophobic macromolecular monomer having an end group which is copolymerizable with the hydrophilic monomer. The resulting copolymer is a graft copolymer characterized as having a comb-type structure consisting of a hydrophilic polymer backbone with hydrophobic polymer side chains bonded thereto. The side chains are disclosed as being bonded to the hydrophilic polymer at only one end of the side chain, so that no network results.
In addition, U.S. Pat. No. 5,807,944 to Hirt et al. discloses an amphiphilic segmented copolymer of controlled morphology comprising at least one oxygen permeable polymer segment and at least one ion permeable polymer segment, wherein the oxygen permeable segments and the ion permeable segments are linked together through a non-hydrolyzable bond. The oxygen permeable polymer segments are selected from polysiloxanes, perfluoroalkyl ethers, polysulfones, and other unsaturated polymers. The ion permeable polymers are selected from cyclic imino ethers, vinyl ethers, cyclic ethers, including epoxides, cyclic unsaturated ethers, N-substituted aziridines, xcex2-lactones, xcex2-lactanes, ketene acetales, vinyl acetates and phosphoranes.
U.S. Pat. No. 5,800,828 to Dionne et al. discloses immunoisolatory vehicles having a core and a surrounding jacket that is capable of secreting a biologically active product or of providing a biological function to a patient, said vehicle being permselective, biocompatible, and having a molecular weight cutoff permitting passage of molecules between the patient and the core of the vehicle, and wherein the jacket is selected from polyacrylonitrile-polyvinylchloride, polyacrylonitrile, poly(methyl methacrylate), poly(vinyl difluoride), polyolefins, polysulfones and celluloses.
The amphiphilic networks taught in the prior art, while suitable for biomedical applications, have tensile strengths that are rather low, namely less than or equal to about 0.5 MPa. It is therefore desirable in the art to develop amphiphilic networks, and implantable biological devices comprising the amphiphilic networks that have superior immunoisolatory properties, superior mechanical properties, and which are biocompatible, hemocompatible, and that exhibit excellent biostability when placed into a host individual for extended periods of time.
It is, therefore, an object of the present invention to provide an amphiphilic network.
It is another object of the present invention to provide an amphiphilic network, as above, that can encase biologically active moieties.
It is another object of the present invention to provide an amphiphilic network, as above, that is immunoisolatory, i.e., networks that can selectively regulate the passage of biological material into, out of, and through the network.
It is another object of the present invention to provide an amphiphilic network, as above, that is biocompatible with a host individual.
It is another object of the present invention to provide an amphiphilic network, as above, that exhibits excellent biostability once implanted into a host individual.
It is another object of the present invention to provide an amphiphilic network, as above, that is hemocompatible with a host individual.
It is another object of the present invention to provide an amphiphilic network, as above, that is readily sterilizable.
It is another object of the present invention to provide an amphiphilic network, as above, that is easily retrievable from a host individual after implantation in an individual.
It is another object of the present invention to provide an amphiphilic network, as above, that exhibits excellent mechanical properties.
It is another object of the present invention to provide an amphiphilic network, as above, that is swellable in both hydrophilic and hydrophobic solvents.
It is another object of the present invention to provide an implantable biological device that can encase biologically active substances and immunoisolate said biologically active substances from the immunological response of the host individual.
It is another object of the present invention to provide a method for the treatment of Type I diabetes mellitus.
These and other objects, together with the advantages thereof over the amphiphilic networks and biological devices comprising amphiphilic networks of the existing art, which shall become apparent from the specification which follows, are accomplished by the invention as hereinafter described and claimed.
In general, the present invention provides an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers, wherein the hydrophobic crosslinking agents are tri-telechelic three-arm polyisobutylenes, having acrylate or methacrylate caps represented by formula (I); 
wherein R1 is an isobutylene polymer represented by formula (II): 
wherein x is the degree of polymerization of isobutylene and R2 is hydrogen or a methyl group;
wherein A is a moiety that connects R1 to the acrylate or methacrylate end caps;
and wherein the hydrophilic monomers are derived from an acrylate selected from the group consisting of formulas (II), (IV) and (V): 
wherein R3 is hydrogen or methyl, R4 is an alkylene group having from about 2 to about 4 carbon atoms, and R5 and R6 may be the same or different and each is hydrogen or an alkyl radical having 1 to about 4 carbon atoms.
The present invention also provides a method of forming an amphiphilic network comprising the steps of:
copolymerizing and crosslinking hydrophilic monomers, wherein the hydrophilic monomers are derived from an acrylate selected from the group consisting of formulas (III), (IV) and (V): 
wherein R3 is hydrogen or methyl, R4 is an alkylene group having from about 2 to about 4 carbon atoms, and R5 and R6 may be the same or different and each is hydrogen or an alkyl radical having 1 to about 4 carbon atoms; and
with hydrophobic crosslinking agents, wherein the hydrophobic crosslinking agents are three-arm star polyisobutylenes, having acrylate or methacrylate end caps represented by formula (I): 
wherein R1 is an isobutylene polymer represented by formula (II): 
wherein A is a moiety that connects R1 to the acrylate or methacrylate end caps;
wherein R2 is hydrogen or a methyl group, and wherein x is the degree of polymerization of isobutylene.
The present invention further provides an implantable biological device that is capable of encapsulating biologically active moieties, and immunoisolating said moieties from the immunological response of a host individual, the device comprising an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers, wherein the hydrophobic crosslinking agents are three-arm star polyisobutylenes, having acrylate or methacrylate end caps represented by formula (I): 
wherein R1 is an isobutylene polymer represented by formula (II): 
wherein A is a moiety that connects R1 to the acrylate or methacrylate end caps;
wherein R2 is hydrogen or a methyl group and wherein x is the degree of polymerization of isobutylene;
and wherein the hydrophilic monomers are derived from an acrylate selected from the group consisting of formulas (III), (IV) and (V): 
wherein R3 is hydrogen or methyl, R4 is an alkylene group having from about 2 to about 4 carbon atoms, and R5 and R6 may be the same or different and each is hydrogen or an alkyl radical having 1 to about 4 carbon atoms.
The present invention further provides a method for the production of an implantable biological device, the device capable of encasing and immunoisolating biologically active moieties upon implantation into a host individual, comprising the steps of forming an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers, wherein the hydrophobic crosslinking agents are three-arm star polyisobutylenes, having acrylate or methacrylate end caps represented by formula (I): 
wherein R1 is an isobutylene polymer represented by formula (II): 
wherein A is a moiety that connects R1 to the acrylate or methacrylate end caps;
wherein R2 is hydrogen or a methyl group and wherein x is the degree of polymerization of isobutylene;
and wherein the hydrophilic monomers are derived from an acrylate selected from the group consisting of formulas (III), (IV) and (V): 
wherein R3 is hydrogen or methyl, R4 is an alkylene group having from about 2 to about 4 carbon atoms, and R5 and R6 may be the same or different and each is hydrogen or an alkyl radical having 1 to about 4 carbon atoms; and forming said amphiphilic network into a desired three-dimensional geometric shape.
The present invention further provides a method for treating Type I diabetes in a diabetic host individual comprising the steps of providing an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers, wherein the hydrophobic crosslinking agents are three-arm star polyisobutylenes, having acrylate or methacrylate end caps represented by formula (I); 
wherein R1 is an isobutylene polymer represented by formula (II): 
wherein A is a moiety that connects R1 to the acrylate or methacrylate end caps;
wherein R2 is hydrogen or a methyl group and wherein x is the degree of polymerization of isobutylene;
and wherein the hydrophilic monomers are derived from an acrylate selected from the group consisting of formulas (III), (IV) and (V): 
wherein R3 is hydrogen or methyl, R4 is an alkylene group having from about 2 to about 4 carbon atoms, and R5 and R6 may be the same or different and each is hydrogen or an alkyl radical having 1 to about 4 carbon atoms; forming the amphiphilic network into an elongated tubular device; encasing a sufficient amount of pancreatic islet of Langerhans cells within the tubular device, wherein the tubular device is capable of immunoisolating the encased islet cells upon implantation into an individual; implanting the tubular device into a diabetic host individual; allowing the implanted tubular device to remain implanted in the diabetic individual for a time sufficient to normalize the blood/glucose level in the diabetic individual.